The overall goal of this project is to develop an enhanced imaging technology using innovative convergent- beam collimation with 3D helical paths (HPs) for quantitative single photon emission computedtomography (SPECT). Promising SPECT molecular imaging agents are being developed for diagnosis of brain diseases such as Parkinson's disease. Full-cone-beam (FCB) SPECT has the potential to be an excellent diagnostic imaging tool for small brain structures, particularly those deep within the brain because of its magnification and its high detection efficiency, which increases with increasing proximity to the focal point. However, SPECT using a FCBcollimator following a circular orbit has two limitations when applied to brain imaging: i) The source distribution is not completely sampled, which results in image artifacts for axial source locations that are not near the collimator's central, transaxial (perpendicular) focal plane; and ii) The caudal region of the brain cannot be imaged effectively because of interferenceof the patient's shoulders with the placement of the collimator. Even SPECT using a FCB collimator following a HP has the latter problem. Both problems are effectively addressed by the innovative combination of offset-astigmatic-beam (OAB) and spatially-variable-focusing (SVF) collimators following HPs: i) Complete spatial sampling can be obtained by using 3D HPs, resulting in high quality, artifact-free reconstructed images from projection data acquired at higher sensitivity and magnification; and ii) Shoulder interference is eliminated. OAB collimators can maintain close proximity to the brain and yet have their offset transaxial focal line positioned near the brain's caudal region. The proposed research will involve experimental scans, as well as computer simulations and analytic calculations. An existing triple-camera SPECT systemand novel convergent-beam collimators, coupled with bed translation, will be used to demonstrate the innovative imaging technique. Iterative reconstruction software will be developed for helical-path OAB and SVF projection data. A laser alignment system and SPECT acquisitions of point sources will be used to determine parametersthat describe system calibrations and mechanical and electrical misalignments of the SPECT scanner. Initially, uniformity of spatial sampling will be investigated using acquisitions that simulate two or three convergent-beam collimators versus the use of a single convergent-beam collimator. State-of-the-art reconstruction programs will account for the effects of system misalignments, point-spread-response, attenuation and scatter. The effects of these factors on image resolution, quantification and artifactswill be evaluated using a selection of geometric and anthropomorphic phantoms. A pilot clinical study will involve a small number of human subjects. This proposal supports the research and development of new imaging techniques, and the results will provide data upon which significant translational research can be built. In the long term, the new techniques will potentially provide better health care through improved diagnosis of brain disease.